Summary Sex bias in human disease is common, however underlying mechanisms remain unclear. Women have immune advantage relative to men, but also greater auto-immune disease and Alzheimer's Disease. Women's immune advantage is modulated by pregnancy and correlates with escape from X-chromosome inactivation of several key immune regulatory genes. In Drosophila females, mating and male Sex Peptide cause increased reproduction but also inflammation and shortened life span. We have shown that these effects can be reversed by feeding the human drug mifepristone/RU486, yielding +70% increase in median life span, and correlated with altered X-linked gene expression, metabolic re-programming, and altered microbiome. We will test the hypothesis that female reproductive metabolism makes mitochondria more susceptible to bacterial toxins, thereby reducing healthspan and life span. We test conserved genes and pathways, including catecholamine signaling, cholesterol metabolism, and the role of specific microbial metabolites. Methods include florescent transgenic reporter constructs, high- throughput sequencing of microbial genomes and fly transcriptomes, 3D video tracking of fly gene expression and behavior, and testing conserved genes and small molecules for ability to increase life span and reduce inflammation. AIM 1 investigates mechanisms including signaling pathway genes and small molecules. AIM 2 investigates metabolome regulation, and AIM 3 identifies the relevant microbe(s) and metabolites. If successful this research will identify mechanisms for female-specific aging that might be partly conserved in humans, and may identify promising genetic targets and drugs for sex- specific interventions in human inflammation and aging-related disease.